Benzyl Phenylsemicarbazides: A Chemistry-Driven Approach Leading to G Protein-Biased Dopamine D4 Receptor Agonists with High Subtype Selectivity

Many subtype-selective Dopamine Receptor ligands developed for the D₂-D₄ family incorporate a 1-arylpiperazine-derived primary recognition motif, which is connected to a lipophilic moiety occupying an extended binding pocket (EBP) of the receptor via an aliphatic linker of variable lengths. The evaluation of a novel group of Dopamine Receptor ligands now showed that highly subtype-selective ligands [up to K_i(D_4.4) = 0.25 nM, D_2L/D_4.4 = 320, D₃/D_4.4 = 710 for APH199 (17)] can be obtained by choosing a relatively large and conformationally flexible 1-benzyl-1-phenylsemicarbazide substructure to fill the EBP. The novel chemotype APH199 (17) was found to act as a full agonist at the D₄ receptor showing significant bias toward G protein activation over β-arrestin recruitment in comparison to quinpirole.